Peripheral neuropathy is a complex of disorders of the peripheral nervous system resulting from damage to the nerve or to the myelin sheath. The damage is long lasting, usually outlasting the injury that initiates it.
Chemotherapy-induced peripheral neuropathy (CIPN) is a common and potential disabling side effect of many cytotoxic drugs. Chemotherapy-induced neuropathy is related to cumulative dose or dose-intensities (Verstappen et al. 2003 Drugs 63:1549-63).
Currently, CIPN is alleviated only by dose reduction, which may compromise the efficacy of the chemotherapy treatment. Patients who already have neuropathic symptoms due to diabetes mellitus, hereditary neuropathies or early treatment with neurotoxic chemotherapy are thought to be more vulnerable for the development of CIPN.
The vinca-alkaloids (e.g. vincristine and vinblastine), platinum-based compounds (e.g. cisplatin) and taxanes (paclitaxel and docetaxel) are amongst the most important drugs inducing peripheral neurotoxicity (Visovsky C. Cancer Invest. 2003 June; 21(3): 439-51), Quasthoff S, Hartung H P J. Neurol. 2002 January; 249(1): 9-17. Review). These drugs are widely used for treatment of various malignancies such as ovarian, breast cancer, and haematological cancers (Verstappen et al. 2003 Drugs 63(15): 1549).
Vincristine-driven neuropathy is mainly characterized by motor and sensory insufficiency (mixed type of neuropathy). Whilst the underlying mechanism is not
fully understood as yet, it has been described to involve an alteration of anterograde axonal transport, ultimately leading to axonal degeneration. Up to now, treatment of vincristine-driven neuropathy is only palliative, as no efficient therapy has been developed so far.
Cis-dichlorodiamine platinum (cisplatin) is the drug of choice for treatment of germ cell cancers. It is also used adjunctively for other solid tumors but the total dose that can be administered is limited by serious adverse effects including renal toxicity and peripheral neurotoxicity. The incidence of nephropathy, which was dose limiting, has been significantly reduced by chloride diuresis. Problems of peripheral neuropathy appear soon after the drug is introduced. The neuropathy is dose limiting and closely related to total cumulative drug dose. Significant peripheral neurotoxicity is apparent in the majority of adult patients who receive >400-500 mg/m2 of cisplatin. The neuropathy is predominantly sensory with initial complaints of paresthesiae (abnormal sensation as burning, prickling, formication) in the distal extremities, which may progress to severe sensory ataxia. Neuropathological studies have shown loss of large myelinated fibers and evidence of axonal degeneration. The neuropathy may continue to progress for several months after cessation of cisplatin and symptoms may develop 3-8 wk after the last dose of chemotherapy (Thompson et al., (1984) Cancer. 54(7): 1269-75). Studies of tissue platinum assays, monitoring the tissues in which platinum accumulates, revealed the highest platinum concentration in tumor tissue, but similarly high concentrations were found in peripheral nervous tissue. This compared with much lower concentrations in brain. Electrophysiological studies in cancer patients treated with cisplatin confirm that large diameter sensory axons are involved.
Taxol is an effective chemotherapeutic agent extensively used in the treatment of solid tumors such as malignant melanoma and ovarian carcinoma. Nevertheless, peripheral neuropathy caused by taxol is increasingly becoming a dose-limiting problem in cancer treatment (Rowinsky E. K., Chaudhry V., Cornblath D. R, Donehower R. C. Neurotoxicity of taxol (1993). Monogr. Natl. Cancer Inst. 107-115.). Taxol is a plant alkaloid that suppresses microtubule dynamics through binding to tubulin subunits, causing mitotic arrest in dividing cells (Derry W. B, Wilson L., Jordan M. A. Substoichiometric binding of taxol suppresses microtubule dynamics (1995) Biochemistry 34: 2203-2211.), and axonal degeneration in peripheral nerve due to interference with axonal transport (Rowinsky et al., 1993). The resulting neuropathy predominantly affects small sensory fibers, but at higher doses motor and large sensory fiber dysfunction occur (Freilich R. I., Balmaceda C., Seidman A. D., Rubin M., DeAngelis L. M. Motor neuropathy due to docetaxel and paclitaxel (1996). Nutr. Rev. 47: 115-118).
In general, treatment of peripheral neuropathy is symptomatic and has no beneficial effect underlying damage to the nerves (Peltier A C, Russell J W. Recent advances in drug-induced neuropathies. Curr Opin Neurol. 2002 October; 15(5): 633-8). For example, pyridoxine (vitamin B6) is used as a method of nutritional support following peripheral nerve damage, antioxidants (e.g. gamma-linoleic acid, alphalipoic acid, and PKC inhibitors and aldose reductase inhibitors) are used to eliminate toxins which may contribute to peripheral neuropathy, anticonvulsant are used to suppress the pain symptoms. Attempts to prevent vincristine-neuropathy using putative neuroprotective agents such as vitamin B1, vitamin B12, glutamate (Boyle et al. J Pharmacol Exp Ther. 1996 October; 279(1): 410-5.), isoaxonine (Le Quesne et al., J Neurol Neurosurg Psychiatry. 1985 September; 48(9): 933-5.), gangliosides or nerve growth factor (Hayakawa et al., Life Sci. 1994; 55(7): 519-25. 4; Lewis et al. Exp Neurol. 1993 November; 124(1): 73-88.) showed limited success.
In particular, common approaches for treatment of chemotherapy-induced neuropathy include the following: dose and duration-limitation of chemotherapeutic agents, and use of nerve growth factor (NGF) and Glutamine (Peltier A C, Russell J W. Recent advances in drug-induced neuropathies. Curr Opin Neurol. 2002 October; 15(5): 633-8).
4-methylcatechol (4-MC) is a catechol derivative having beneficial effects in sciatic nerve regeneration and in two experimental models of diabetic neuropathy [Hanaokoa and Ohi J. Neurolog. 1994 122, 28-32, and Saita et al. J. Pharmacol. Exp. Ther. 1996, 276, 231-237]. Catechol derivatives such as 4-methylcatechol (4-MC), stimulate the production of nerve growth factor (NGF) from cultured astrocytes in vitro and in vivo [Takeuchi et al. FEBS Lett 1990, 261, 63-66] and induce brain-derived neurotrophic factor (BDNF) in rat brain [Nitta et al J. Pharmacol. Exp. Ther. 1999, 291, 1276-83]. However, the therapeutic utility of catechols is not clear, since they are reactive chemicals and may produce numerous side effects or drug-drug interaction at therapeutic concentrations (Schweigert et al. 2001 Environmental Microbiology Volume 3 Issue 2 Page 81).
IL-6 acts not only as a pro—but also as an anti inflammatory cytokine (Jones et al. FASEB J. 2001 January; 15(1): 43-58. Review). The functional properties of IL-6 are extremely varied and this is reflected by the terminology originally used to describe this cytokine (Horst Ibelgaufts' COPE: Cytokines Online Pathfinder Encyclopaedia).
Two proteins bind IL-6, IL-6 receptor (IL-6R) and gp130 (reviewed by Hirano et al Stem Cells. 1994 May; 12(3): 262-77. Review). Soluble forms of IL-6R (sIL-6R), corresponding to the extracellular domain of gp80, are natural products of the human body found as glycoproteins in blood and in urine (Novick et al, J. Chromatogr. 1990 27; 510:331-7, and Cytokine. 1992 January; 4(1): 6-11). An exceptional property of sIL-6R molecules is that they act as potent agonists of IL-6 on many cell types including human cells (Taga et al, Cell. 1989 11; 58(3): 573-81, Novick et al. 1992 4(1): 6-11). Even without the intracytoplasmic domain of gp80, sIL-6R is still capable of triggering the dimerization of gp130 in response to IL-6, which in turn mediates the subsequent IL-6-specific signal transduction and biological effects (Murakami Science. 1993 Jun. 18; 260(5115): 1808-10). sIL-6R has two types of interaction with gp130 both of which are essential for the IL-6 specific biological activities (Halimi et al., Eur Cytokine Netw. 1995 May-June; 6(3): 135-43), and the active IL-6 receptor complex was proposed to be a hexameric structure formed by two gp130 chains, two IL-6R and two IL-6 ligands (Ward et al., 1994; Paonessa et al, EMBO J. 1995 May 1; 14(9): 1942-51).
In contrast to the expression of the cognate IL-6R which has a limited cellular distribution (Jones et al. 2001), expression of the trans-membrane-spanning gp130 is found in almost all organs, including heart, kidney, spleen, liver, lung, placenta, and brain (Saito et al J. Immunol. 1992 Jun. 15; 148(12): 4066-71).
There are many different examples, which show that IL-6 alone does not induce a specific activity unless the soluble IL-6R is administered. For example, IL-6 induces osteoclast formation in co-cultures of mouse bone marrow and osteoblastic cells, only when combined with the sIL-6R (Jones et al. 2001). Also, although many neuronal cells are capable of producing IL-6, they remain unresponsive to stimulation by IL-6 itself. Differentiation and survival of neuronal cells can, however, be mediated through the action of sIL-6R (Hirota J Exp Med. 1996 Jun. 1; 183(6): 2627-34. Martz Cheng, J.-G., Gadient, R. A., Patterson, P. H., Stoyan, T., Otten, U., Rose-John, S. (1998) Sympathetic neurons can produce and respond to interleukin-6. Proc. Natl. Acad. Sci. USA 95, 3251-3256).
The circulating concentrations of sIL-6R (agonist) in normal subjects are relatively high and comparable to those of soluble gp130 (a natural antagonist of IL-6), of above 10 ng/ml (Corbi et al 2000 Eur J Cardiotherac Surg. 18 (1): 98-103, Disthabanchong et al. Clin Nephrol. 2002 October; 58(4): 289-95). In contrast, the circulating concentrations of IL-6 are about or below 10 pg/ml (Kado et al. 1999 Acta Diabetol. June 36 (1-2)67-72, Corbi et al 2000. Thus the effect of IL-6 administration in vivo, alone, without co-administration with sIL-6R in disease may or may not be effective and depends on the concentration of the soluble agonist/antagonist in a particular disease and in a particular location in the body.
Chimeric molecules linking the soluble IL-6 receptor and IL-6 together have been described (Chebath et al. Eur Cytokine Netw. 1997 December; 8(4): 359-65). They have been designated IL-6R/IL-6 chimera. The chimeric IL-6R/IL-6 molecules were generated by fusing the entire coding regions of the cDNAs encoding the soluble IL-6 receptor (sIL-6R) and IL-6. Recombinant IL-6R/IL-6 chimera was produced in CHO cells (Chebath et al, Eur Cytokine Netw. 1997, WO99/02552). The IL-6R/IL-6 binds with a higher efficiency to the gp130 chain in vitro than does IL-6 with sIL-6R (Kollet et al, Blood. 1999 Aug. 1; 94(3): 923-31).
As mentioned above, interleukin-6 signaling is facilitated through the homodimerization of gp130 to the ligand-receptor complex. Intracellular signaling is subsequently triggered via activation of gp130-associated cytoplasmic tyrosine kinases (JAK1, JAK2, and TYK2) and phosphorylation of STAT1 and STAT3 (Murakami et al Science. 1993 Jun. 18; 260(5115): 1808-10. Gerhartz et al. J Biol Chem. 1996 May 31; 271(22):12991-8). In contrast, the high-affinity receptors of LIF, OSM, and CNTF activate cells by a heterodimerization between gp130 and a gp130-related protein (the LIF receptor) (Davis et al. Science. 1993 Jun. 18; 260(5115): 1805-8). Such homo- or heterodimers activate distinct but overlapping patterns of tyrosine phosphorylation through the Jak-Tyk family of cytoplasmic tyrosine kinases (Boulton et al. J Biol Chem. 1994 Apr. 15; 269(15): 11648-55). This may contribute to the different cellular responses associated with this family of proteins.
The therapeutic effect of recombinant IL-6 alone without the soluble IL-6R in an animal model of diabetes-induced neuropathy has been disclosed in patent application WO03033015. However, it is uncertain whether in a different type of peripheral neuropathy such as chemotherapy-induced peripheral neuropathy (CIPN) IL-6, administrated alone without the soluble IL-6R, is capable of a therapeutically and/or a preventive effect.
In phase I clinical trials of hrIL-6 in patients with myelodysplastic syndromes and trombocytopenia the maximum dose tolerated was found to be 3.75 μg/kg/d (Gordon et al. Blood 1995 85 (11): 3066-76.
It is uncertain whether a low dose of IL-6, which may preclude toxicity, is efficient in preventing and or curing and/or ameliorating chemotherapy-induced neuropathy.
Recombinant leukemia inhibitor factor (LIF), another gp130 activator, was tested in clinical trials for preventing CIPN caused by carboplatin/paclitaxel assessed by composite peripheral nerve electrophysiology (CPNE) score, based on nerve velocity, amplitude and H-reflex latency, vibration perception threshold and symptom scores (2003, ASCO annual meeting Abstract number 2976). In these studies either 2 or 4 μg/kg LIF were given sub coetaneous daily for 7 days starting the day prior to carboplatin/paclitaxel. The results of the clinical trials indicated that LIF was ineffective at preventing CIPN at the doses and regime tested.
Therefore, new drugs/strategies for preventing/treating peripheral neuropathy caused by a wide range of chemotherapy agents are thus needed.